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At least 19 recordsLinked to original sources
PubMed2026

An EHR-based framework for modeling growth curves and constructing growth centile charts for genetic disorders.

Growth modeling is central to human genetics, as deviations from typical growth can signal an underlying disorder. In this cohort study, we developed a generalizable framework for generating growth charts across genetic conditions using electronic health records (EHR). Leveraging 22 years of longitudinal EHR data from 452,470 patients across 15 genetic conditions and unaffected individuals, we generated sex- and condition-specific growth charts using Generalized Additive Models for Location, Scale, and Shape, and quantified differences in size, timing, and intensity using SuperImposition by Translation and Rotation (SITAR). SITAR-derived growth parameters showed strong concordance with established annotations in OMIM and Orphanet, and identified previously unreported growth patterns. We stratified cystic fibrosis by CFTR functional class and observed greater growth impairment in individuals with homozygous minimal-function variants compared to those with residual function. This framework provides a generalizable approach for leveraging EHR data to refine genotype-phenotype relationships and enable continuous updating of growth charts across genetic conditions.

Journal Article↗
PubMed2026

Whole-exome Sequencing Identifies Novel Candidate PCNT Variants in a Child With Overlapping MOPD II Features: A Case Report.

A 7-year-old Chinese boy presented with severe postnatal growth failure (height <3rd percentile at age 7 years), global developmental delay, moderate intellectual disability, and characteristic dysmorphic features including hypertelorism, short palpebral fissures, low-set ears, and a broad nasal bridge. A single electrocardiogram demonstrated a borderline corrected QT interval (QTc = 450 ms). No arrhythmias, QT-prolonging medications, electrolyte abnormalities, or relevant family cardiac history were identified. This finding warrants longitudinal cardiology follow-up and should not be interpreted as definitive Long QT syndrome. Whole-exome sequencing identified two novel missense variants in the PCNT gene (NM_006031.5): c.5675A>G (p.Glu1892Gly) in exon 28 and c.9734G>T (p.Arg3245Ile) in exon 45. Both variants were absent from gnomAD, ExAC, the 1000 Genomes Project database, and Chinese population databases, fulfilling ACMG criterion PM2. Although classified as variants of uncertain significance (VUS) because of limited functional evidence and conflicting in silico predictions, the variants occur in a gene associated with primordial dwarfism and are accompanied by partial phenotypic overlap with Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II). However, parental segregation analysis was unavailable; therefore, the variant phase could not be confirmed, and a recessive disease mechanism could not be established. These findings support the presence of candidate PCNT variants in an atypical primordial dwarfism phenotype and illustrate the utility of whole-exome sequencing for generating testable molecular hypotheses in genetically heterogeneous growth disorders. A definitive molecular diagnosis cannot be established at present, and the isolated borderline QTc finding requires further clinical evaluation.

Humans↗
PubMed2026

Familial short stature: genetic architecture, risk stratification, and precision management.

BACKGROUND: Familial short stature (FSS) has traditionally been considered a benign growth pattern characterized by short stature clustering within families and has often been regarded as a normal variant of growth. However, recent advances in genomic technologies have demonstrated that a subset of children presenting with an FSS phenotype harbor identifiable monogenic variants, particularly in genes involved in growth plate development and skeletal growth. These findings challenge the traditional phenotype-based understanding of FSS and support an etiology-oriented diagnostic framework. OBJECTIVE: To summarize current knowledge regarding the genetic architecture of FSS, review existing clinical risk stratification frameworks for genetic evaluation, and evaluate available evidence regarding treatment outcomes across different genetic etiologies. METHODS: A literature search was performed in PubMed, Embase, and Web of Science from inception to May 2026, using keywords including "familial short stature," "familial idiopathic short stature," "genetic testing," "ACAN," "SHOX," and "NPR2". Relevant original studies and review articles addressing genotype-phenotype correlations, diagnostic yield of genetic testing, or responses to recombinant human growth hormone (rhGH) therapy were considered. RESULTS: Emerging evidence indicates that monogenic variants can be identified in a subset of children with an FSS phenotype, especially among those with more severe short stature and autosomal dominant inheritance patterns. Variants affecting growth plate biology represent some of the most frequently reported genetic causes of FSS, with ACAN, SHOX, and NPR2 being the most frequently implicated genes. Existing clinical frameworks based on parental height patterns and inheritance characteristics may help stratify patients with FSS according to the likelihood of monogenic etiology and guide selection of individuals who may benefit from genetic testing. Available evidence suggests that rhGH therapy may improve growth outcomes in several monogenic forms of FSS, although treatment responses vary according to genetic etiology. CONCLUSIONS: FSS should be regarded as a heterogeneous clinical phenotype rather than a single diagnostic entity. Integration of existing clinical risk stratification approaches with molecular diagnosis may enable more precise identification of underlying genetic causes and facilitate individualized therapeutic decision-making. Future advances in FSS management will likely depend on precision medicine approaches linking phenotype, genotype, and treatment response.

Humans↗
PubMed2026

Analysis of Genetic Factors in a Family With Short Stature.

BACKGROUND: To elucidate the genetic underpinnings of short stature in a familial cohort of five individuals. METHODS: A family with a history of short stature from Zhongnan Hospital of Wuhan University was the subject of this study. Peripheral blood samples were collected from family members for whole exome sequencing and Sanger sequencing to identify genetic anomalies. RESULTS: The male proband, aged 3&#x2009;years and 10&#x2009;months, had significant growth retardation, with a height of 91&#x2009;cm (<&#x2009;3rd percentile) and a weight of 13&#x2009;kg (<&#x2009;3rd percentile). Whole exome sequencing identified a missense mutation in the COL1A2 gene (c.577G>A, p.Gly193Ser) with maternal inheritance. Sanger sequencing confirmed this mutation in the mother and half-sister. According to American College of Medical Genetics and Genomics (ACMG) guidelines, this variant was classified as likely pathogenic. Additionally, a heterozygous mutation in the GH1 gene (c.291+1G>A) was detected in the father and grandfather, contributing to the familial short stature phenotype. CONCLUSION: In this family, we identified that variants in the COL1A2 and the GH1 can each cause short stature. This reflects both the genetic consistency and complexity of short stature, which is highly dependent on comprehensive genetic testing.

Humans↗
PubMed2025

Isolated lateralized overgrowth and the need for tumor screening: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: To provide diagnostic guidance for individuals with lateralized overgrowth (LO) and implement appropriate screening protocols. LO without a syndromic presentation is considered idiopathic isolated lateralized overgrowth (ILO). METHODS: We performed a literature search of LO syndromes and malignancy risk and reviewed existing guidelines and expert input. RESULTS: We integrated 940 unique articles to form recommendations. We defined LO as significantly larger length and/or girth of aspect(s) of one side of the body compared with its contralateral side. It can be associated with somatic overgrowth syndromes. ILO was previously defined based on clinical features and deemed idiopathic by absence of molecular findings. Much of the tumor risk is likely because of specific LO syndromic causes now identified through improved diagnostic technologies; therefore, the tumor risk in idiopathic ILO is likely lower than previously accepted. CONCLUSION: Mosaicism complicates molecular diagnosis for children with LO. However, conditions such as Beckwith-Wiedemann spectrum and PTEN-related hamartoma tumor syndrome necessitate routine tumor screening. Establishing a specific diagnosis via comprehensive molecular testing on affected tissue will guide screening and management. In cases of idiopathic ILO, location of the overgrowth, estimation of tumor risk, regional practice approaches and family concerns all play roles in determining tumor screening.

Child↗
PubMed2026

Endocrine Phenotypes and Hormonal Treatment in Meier-Gorlin Syndrome: Report of Two Cases and a Systematic Review of Literature.

BACKGROUND: Meier-Gorlin-syndrome (MGORS) is a rare cause of primordial dwarfism stemming from pathogenic variants in genes involved in DNA replication. The classic clinical triad is microtia, absent patella and short stature. MGORS can mimic endocrine causes of short stature or delayed/atypical pubertal development. METHODS: We report two new cases of MGORS. A systematic literature search of all cases published up to 31 March 2026 was done to identify the cases reporting any endocrinopathy or hormonal therapy, focussing on growth-hormone-deficiency (GHD) and response to growth hormone (GH). RESULTS: We describe a 14 year-old girl, the first MGORS case with CDC6 variant and mammary hypoplasia. Another 11-year old boy with GMNN variant had severe short-stature with GHD and had significant height improvement with GH. Among 29 cases (out of ~150 published), the classic triad was absent in 18.5%. Short stature was almost universal (median height-Z-score -4.4), with 70% exhibiting delayed bone age, 42.9% low IGF-1 and 35.3% GHD. Among 10 GH-treated cases with response data, 6 had reported improvement in height-SDS/growth-velocity. Those with GHD and delayed bone age were more likely to benefit from GH. Among females, all post-pubertal cases had mammary hypoplasia, while 23.5% had clitoromegaly with hypoplastic labia. Among males, cryptorchidism, hypoplastic scrotum and micropenis were common. However, gonadal hormones and gonadotrophins were normal. Data on the effect of estrogen on hypoplastic mammary glands or labia was variable. CONCLUSION: MGORS should be kept in mind as a differential of multiple endocrinopathies. Cases of MGORS should undergo screening for GHD. Available data, mostly from case-reports or small series, suggest that response to GH has been reported in some individuals, particularly where GHD or delayed bone age was present, but evidence remains very limited.

Humans↗
PubMed2026

Histidine Supplementation Stabilizes Hearing and Vision and Improves Growth in HARS1-Related Autosomal Recessive Disorder Associated With Usher-Like Symptoms.

Autosomal recessive HARS1-related disorder (originally described as Usher syndrome type 3B) caused by a homozygous Y454S variant in the histidyl-tRNA synthetase gene (HARS1) is characterized by progressive sensorineural hearing and vision loss and respiratory deterioration with risk for sudden death following febrile illnesses. In-vitro studies have previously shown that histidine can rescue a humanized yeast model for pathogenic HARS alleles. Fourteen children homozygous for HARS Y454S were treated with supplemental oral histidine (50 mg/kg BID) and monitored with bloodwork and physical, visual, and audiometry assessments during a 3-year clinical trial, then followed for more than 4&#x2009;years on histidine in the post-trial period. Patient fibroblasts were assessed for response to histidine. Hearing and vision remained stable, and growth improved significantly. Children remained healthy, with no severe deteriorations despite exposure to bacterial and viral infections, including COVID-19. Gains in growth were maintained in the post-trial period on varying levels of histidine supplementation. Daily oral histidine supplementation in children with autosomal recessive HARS1-related disorder can ameliorate or slow the progression of disease and is safe, inexpensive, and well tolerated. This study adds to the growing list of autosomal recessive ARSopathies (aminoacyl-tRNA synthetase disorders) that are amenable to amino acid supplementation.

Humans↗
PubMed2026

The SPL-family transcription factor MpSPL3 orchestrates the proper regulation of vegetative and reproductive programs in Marchantia polymorpha.

SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) genes encode plant-specific transcription factors that are widely distributed across the plant kingdom. In angiosperms, the multimember SPL family regulates various biological processes, including vegetative-to-reproductive phase transition, inflorescence architecture, and lateral organ development. In contrast, the liverwort Marchantia polymorpha genome encodes only four SPL genes, with functional studies available only for microRNA-targeted members, MpSPL1 and MpSPL2. MpSPL1 was shown to control the meristem dormancy to modulate the thallus architecture, whereas MpSPL2 was found to promote the transition from vegetative-to-reproductive phase. Here, we investigate the impact of the MpSPL3 gene on M. polymorpha development. We demonstrate that MpSPL3 influences coordination of the vegetative growth and the reproductive phase transition. Knockout of MpSPL3 leads to strong growth retardation with disordered thallus morphology, reduced gemma cup number, and, most strikingly, complete loss of gametangiophore formation. Interestingly, overexpression of MpSPL3.2, the shorter isoform, has no detectable morphological effect, whereas the overexpression of MpSPL3.1, the longer isoform encoding a protein with an additional 61-aa long fragment, results in a delay in timing and reduced efficiency of gametangiophore production. Moreover, all the observed developmental abnormalities might be a consequence of the altered expression of genes essential for proper vegetative development and responsible for germ cell specification in MpSPL3 knockout and overexpression plants. Altogether, our findings demonstrate that MpSPL3 is important in regulating gametophyte development and ensuring reproductive success in M. polymorpha.

Marchantia↗
PubMed2026

Chiari I malformation.

Chiari I malformation (CM1), the most common structural hindbrain disorder in humans, is traditionally characterized by the downward displacement of the cerebellar tonsils through the foramen magnum. However, this definition does not reflect the variability in clinical presentation, natural history and treatment response of this disorder. Some individuals with minimal tonsillar descent have severe neurological symptoms and syringomyelia, whereas others with extensive descent remain asymptomatic. Emerging evidence from neuroimaging, developmental biology and human genetics indicates that CM1 is not a single anatomical entity but a spectrum of disorders resulting from disruptions in coordinated growth and homeostasis across the cerebellum, posterior fossa, craniocervical junction, cerebrospinal fluid and neurovascular systems. CM1 may be best understood as a disorder of disrupted developmental scaling, in which the tightly regulated relationships between cerebellar growth and cranial accommodation are altered within a dynamic neurovascular and cerebrospinal fluid environment. In this context, tonsillar herniation is a geometric consequence rather than the primary disease process. This Primer synthesizes current knowledge on the epidemiology, mechanisms, diagnosis and management of CM1 across the lifespan. We highlight advances in neuroimaging, genomics and phenomics that support a shift from anatomy-based definitions towards an integrated genomic-phenomic classification.

Humans↗
PubMed2023

Structural and functional insights into a novel homozygous missense pathogenic variant in CUL7 identified in consanguineous Pakistani family.

3M syndrome is a rare genetic familial disorder characterized by short stature, growth retardation, facial dysmorphism, skeletal abnormalities, fleshy protruding heels, and normal intelligence, caused by mutations in the CUL7, OBSL1 and CCDC8 genes. In the present study, a novel homozygous missense variant of CUL7 (NP_001161842.1, c.4493T&#x2009;>&#x2009;C, p.L1498P) has been identified in a consanguineous Pakistani family by whole exome sequencing. In silico structural evaluation, molecular docking and simulation studies of mutant CUL7 provides substantial evidence about its crucial role in the progression of discussed ailment. The newly discovered variant significantly altered the protein's three dimensional structure, leading to abnormal interaction with binding proteins. This computational and experimental investigation provides useful information to drug developers for the synthesis of novel therapeutics against the discussed ailment.Communicated by Ramaswamy H. Sarma.

Humans↗
PubMed2026

A Novel Splice Variant in the COL1A1 Gene Leads to Exon 46 Skipping and Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a clinical and genetic disorder characterised by bone fragility, growth deficiency and skeletal deformity. Ninety per cent of OI cases are attributable to autosomal dominant variants in the COL1A1 and COL1A2 genes. METHODS: Candidate variants were identified and verified through trio whole-exome sequencing (trio-WES), copy number variation sequencing (CNV-seq) and Sanger sequencing. Minigene splicing assays were performed in HeLa and HEK293T cells with pcDNA3.1 and pcMINI-C vectors to investigate the function of the candidate variants. A systematic review of COL1A1 splicing variants and the corresponding genotype-phenotype spectrum was performed. RESULTS: Trio-WES revealed a novel heterozygous variant in the C-terminal region of the COL1A1 gene: NM_000088.4:c.3423+5G>A. Sanger sequencing confirmed the variant in both the proband (II-2) and her foetus (III-1) who were clinically suspected of having OI. The c.3423+5G>A variant causes complete skipping of Exon 46, as demonstrated by a minigene splicing assay. We retrieved 419 COL1A1 splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers-Danlos syndrome and stratified the remaining 402 variants into three types on the basis of splice site location: (1) Variants at canonical splicing sites (77.8%, 313/402) mostly cause mild phenotypes, whereas a minority may be severe. (2) Intron variants in other locations, such as splice region variants (17.9%, 72/402), usually cause mild clinical phenotypes, and deep intronic splice variants (0.4%, 2/402) that may result in severe phenotypes. (3) Other variants (3.7%, 15/402), such as exon variants or fragment loss, are extremely rare. We also preliminarily discuss the mechanisms underlying phenotypic variability and the characteristics of C-terminal variants. CONCLUSIONS: This intron variant in COL1A1 was classified as likely pathogenic and was confirmed to disrupt COL1A1 expression. The summary analysis results also revealed a correlation among splicing variants, C-terminal region variants and disease, suggesting that variant location provides a useful framework for prognosis prediction.

Female↗
PubMed2026

Biliary Cirrhosis in Myhre Syndrome: The First Case Report of Liver Transplantation and a Review of Reported Hepatic Findings.

Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function pathogenic variants in SMAD4 and is now recognized as a progressive multisystem fibrotic disease. Although transforming growth factor-&#x3b2; (TGF-&#x3b2;) signaling plays a central role in hepatic fibrogenesis, hepatobiliary involvement in Myhre syndrome has not been systematically evaluated. We report the first case of Myhre syndrome complicated by rapidly progressive biliary cirrhosis requiring liver transplantation in a 15-year-old male with a confirmed SMAD4 p.Ile500Val variant. Following an infectious episode, the patient developed severe cholestasis with imaging and histopathologic findings consistent with fibro-obliterative cholangiopathy, ultimately necessitating living donor liver transplantation. A systematic review of 55 published reports comprising 217 patients with Myhre syndrome revealed that hepatic evaluation was rarely performed and that previously reported liver abnormalities were mild and secondary, most commonly related to right heart dysfunction or metabolic disease, with no prior cases of progressive biliary fibrosis. This case suggests that dysregulated SMAD4-TGF-&#x3b2; signaling may predispose selected organs to fibro-obliterative injury and that infection-driven inflammation may act as a critical trigger for hepatic fibrosis in Myhre syndrome, expanding the recognized spectrum of organ involvement in this disorder.

Humans↗
PubMed2024

Dual diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly.

BACKGROUND: Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 (FGFR3) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient's symptoms, opening new avenues for diagnosis and management. CASE PRESENTATION: We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). CONCLUSION: This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.

Humans↗
PubMed2026

A Case Report of Infantile Dopa-Responsive Dystonia Onset With Sleep Disorder Complicated With Autism Spectrum Disorder.

AIMS/BACKGROUND: Dopa-responsive dystonia (DRD) is a rare genetic disorder with complex and diverse clinical manifestations, resulting in a high rate of misdiagnosis. This case report describes an infantile case of DRD complicated by autism spectrum disorder (ASD), initially presenting with a sleep disorder. We aim to summarize its clinical manifestations, diagnostic process, treatment, and follow-up outcomes in order to improve clinical understanding of this disease. CASE PRESENTATION: A retrospective analysis was performed on a male infant who was treated at Jinhua Maternal and Child Health Care Hospital in 2020. The patient presented at one month of age with sleep disturbances, delayed motor development, and intermittent upward deviation of the eyes. Genetic testing identified two heterozygous pathogenic variants in the tyrosine hydroxylase (TH) gene. Among them, the c.738-2A>G variant was not recorded in the Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD), or 1000 Genomes Asian population databases. During follow-up, the patient was also found to have comorbid ASD. RESULTS: Genetic testing confirmed biallelic TH mutations, establishing the diagnosis of infantile DRD. The patient exhibited marked clinical response to levodopa/benserazide, though dose titration was required with growth. CONCLUSION: For infants with unexplained sleep disorder accompanied by delayed motor development, genetic testing should be performed as early as possible to facilitate the identification of the root cause and implement timely treatment. In addition, close follow-up should be conducted to detect comorbid neurodevelopmental disorders.

Humans↗
PubMed2026

Experiences and Behavior During a Virtual Reality Buffet Simulation: A Secondary Analysis of a Ghrelin-Related Pharmacology Randomized Controlled Trial in People with Alcohol Use Disorder.

BACKGROUND: Virtual reality (VR) can deliver standardized, ecologically valid assessments while capturing nuanced psychological and behavioral outcomes. Sensitivity of VR assessments to pharmacological interventions, however, has seldom been tested. METHODS: We conducted a secondary analysis of a randomized, double-blind, placebo-controlled, crossover study evaluating a growth hormone secretagogue receptor (GHSR, the ghrelin receptor) blocker (PF-5190457) in people (N = 29) with alcohol use disorder. The previously reported primary study results demonstrated that the GHSR blocker did not reduce alcohol cue-elicited craving but did reduce the number of calories selected in a VR buffet food choice assessment. Here, we investigated the impact of the drug on experiences and behavior in the VR buffet. RESULTS: Participants reported higher levels of liking the VR, more typicality, and more satisfaction with their food choices under the GHSR blocker than the placebo. We also found that participants who were given the placebo first took longer to make a decision about the food they should eat and were also more likely to go up for a second serving of food when on the placebo. This was significantly less likely for participants who were given the GHSR blocker. CONCLUSIONS: The present results suggest that the GHSR blocker influenced experiences and behavior in the VR buffet in ways that are conceptually consistent with the known real-world effects of blocking the ghrelin system. These findings support the validity of using VR buffets as proxies for real-world measurements in pharmacology contexts.

alcohol use disorder↗
PubMed2026

The minor spliceosome component U4atac regulates JAK/STAT signaling to modulate hematopoiesis and immune responses in Drosophila melanogaster.

The small nuclear RNA U4atac is a core component of the minor spliceosome. In humans, homozygous or compound heterozygous point mutations in U4atac cause rare developmental disorders, such as Roifman syndrome, characterized by growth restriction, brain anomalies, and immune deficiency. To better define the pathophysiological role of U4atac mutations, we here establish a model of minor spliceosome dysfunction by generating a Drosophila melanogaster CRISPR/Cas9-induced U4atac mutant in the highly conserved stem II region. U4atac homozygous mutants exhibit growth and neurodevelopmental defects, immunodeficiency, and gastrointestinal symptoms. Using bulk RNA-sequencing and functional assays, we reveal that mutations in U4atac affect the splicing of a large set of transcripts involved in innate immunity, hematopoiesis, and intestinal cell functions, including the Drosophila Janus kinase (JAK) homolog hopscotch (hop). Importantly, U4atac deficiency reduces Hop expression and causes Hop-related hematopoietic defects at the embryonic and larval stages. Notably, we also observe reduced expression of Jak1 and attenuated activation of downstream signaling in patients with Roifman syndrome. Thus, our work identifies alterations of Jak signaling as part of the pathogenesis of RNU4atac-opathy.

Animals↗
PubMed2025

Influence of creatine pyruvate on newly received cattle: insights from metagenomics and metabolomics.

Transport stress is a critical factor affecting the health and growth performance of beef cattle, potentially leading to oxidative stress, inflammation, and metabolic disorders. Creatine pyruvate (CrPyr), as a potential stress alleviator, has unclear mechanisms of action. We monitored the growth of 17 Simmental calves (control, n&#x2009;=&#x2009;8; CrPyr, n&#x2009;=&#x2009;9) over 30 days post-transportation, collecting rumen and blood samples on days 1/4, and 30. This study aims to investigate the effects of CrPyr on the growth performance, rumen microbiome, and metabolome of calves subjected to transport stress. Results showed that CrPyr increased average daily gain and antioxidant capacity, while reducing the level of stress hormones and inflammation. In the 4 days post-transport, CrPyr mainly increases Ruminococcus abundance to boost ruminal nitrogen metabolism, providing substrates for microbial protein synthesis. CrPyr also provides energy for the proliferation of Ruminococcus by regulating ATP synthesis genes (ATPVC) and enriching purine metabolism products. Meanwhile, it strengthens the host's amino acid metabolism, especially aspartate, to enhance antioxidative capacity. By day 30, CrPyr primarily boosts Prevotella abundance to regulate VFA synthesis, supplying host energy. It regulates the ATP synthesis gene ATPF0A and enriches purine metabolism products, supporting Prevotella growth. Increased citric acid and ATP levels further aid host growth. The findings distinctly demonstrate that the mechanisms by which CrPyr alleviates transport stress through the regulation of the rumen microbiome and metabolome, and confirms that its effects are time-dependent. These findings provide a theoretical basis for the development of stress-alleviation strategies based on CrPyr and hold significant implications for enhancing the health and production performance of beef cattle.

Animals↗